Abstract
Reduced clearance of lipoproteins by HDL scavenger receptor class B1 (SR-B1) plays an important role in occlusive coronary artery disease. However, it is not clear how much microvascular dysfunction contributes to ischemic cardiomyopathy. Our aim was to determine the distribution of vascular dysfunction in vivo in the coronary circulation of male mice after brief exposure to Paigen high fat diet, and whether this vasomotor dysfunction involved nitric oxide (NO) and or endothelium derived hyperpolarization factors (EDHF). We utilised mice with hypomorphic ApoE lipoprotein that lacked SR-B1 (SR-B1−/−/ApoER61h/h, n = 8) or were heterozygous for SR-B1 (SR-B1+/−/ApoER61h/h, n = 8) to investigate coronary dilator function with synchrotron microangiography. Partially occlusive stenoses were observed in vivo in SR-B1 deficient mice only. Increases in artery-arteriole calibre to acetylcholine and sodium nitroprusside stimulation were absent in SR-B1 deficient mice. Residual dilation to acetylcholine following L-NAME (50 mg/kg) and sodium meclofenamate (3 mg/kg) blockade was present in both mouse groups, except at occlusions, indicating that EDHF was not impaired. We show that SR-B1 deficiency caused impairment of NO-mediated dilation of conductance and microvessels. Our findings also suggest EDHF and prostanoids are important for global perfusion, but ultimately the loss of NO-mediated vasodilation contributes to atherothrombotic progression in ischemic cardiomyopathy.
Highlights
It is widely recognized that high density lipoprotein (HDL) play an important role in inhibiting the initiation and progression of atherosclerosis through reverse cholesterol transport from cells
Nitrotyrosine levels were more than five times higher in scavenger receptor class B1 (SR-B1)−/−/ApoER61h/h myocardium than in SR-B1+/−/ApoER61h/h (p < 0.001) and frequently elevated in both normal myocardial regions and remodeled regions associated with an occluded vessel in the hearts of SR-B1−/−/ApoER61h/h mice after exposure to the Paigen diet (Fig. 1)
Expression of endothelial nitric oxide synthase (eNOS) protein was clearly evident as a dark brown stain in the endothelium lining of vessels from large coronary arteries to capillaries in both mouse groups (Fig. 2), and there was a non-significant tendency (p = 0.12) for mean myocardial eNOS expression to be higher in SR-B1−/−/ApoER61h/h mice
Summary
It is widely recognized that high density lipoprotein (HDL) play an important role in inhibiting the initiation and progression of atherosclerosis through reverse cholesterol transport from cells. Deficiency in SR-B1 causes accumulation of large cholesterol ester rich HDL particles, reduced antioxidant activity and elevated in vivo isoprostane F2α in plasma, liver and urine as result of oxidation of LDL3. Mice deficient in both SR-B1 and apolipoprotein E (apoE) rapidly develop dyslipidemia, atherosclerosis and spontaneous myocardial infarction on a normal chow diet, resulting in premature death by 6–8 weeks of age[5,6]. Both apoE and SR-B1 are expressed in macrophages which are critical to atherosclerotic lesion formation. We tested the hypothesis that the development of atherosclerosis and ischemic cardiomyopathy in the coronary macro and microcirculations involves impaired NO-mediated dilation, but not EDHF
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